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The Relationship between Benzo[a]pyrene-induced Mutagenesis and Carcinogenesis in Repair-deficient Cockayne Syndrome Group B Mice¹

Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Center, 2300 RA Leiden [S. W. P. W., L. H. F. M., A. A. v. Z., H. V.]; National Institute of Public Health and the Environment (RIVM), Laboratory of Health Effects Research, Department of Carcinogenesis, Mutagenesis and Genetics, [C. T. M. v. O., H. v. S.], Laboratory of Pathology and Immunobiology [R. B. B.], 3720 BA Bilthoven; Department of Cell Biology and Genetics-MGC, Erasmus University Rotterdam, 3000 DR Rotterdam [H. J. M. K., G. T. J. v. d. H.]; and J. A. Cohen Institute, Inter-University Institute for Radiopathology and Radiation Protection, 2300RA Leiden [L. H. F. M., A. A. v. Z., H. V.], the Netherlands

Cockayne syndrome (CS) patients are deficient in the transcription coupled repair (TCR) subpathway of nucleotide excision repair (NER) but in contrast to xeroderma pigmentosum patients, who have a defect in the global genome repair subpathway of NER, CS patients do not have an elevated cancer incidence. To determine to what extent a TCR deficiency affects carcinogen-induced mutagenesis and carcinogenesis, CS group B correcting gene (CSB)-deficient mice were treated with the genotoxic carcinogen benzo(a)pyrene (B[a]P) at an oral dose of 13 mg/kg body weight, three times a week. At different time points, mutant frequencies at the inactive lacZ gene (in spleen, liver, and lung) as well as at the active hypoxanthine phosphoribosyltransferase (Hprt) gene (in spleen) were determined to compare mutagenesis at inactive versus active genes. B[a]P treatment gave rise to increased mutant frequencies at lacZ in all of the organs tested without a significant difference between CSB^-/- and wild-type mice, whereas B[a]P-induced Hprt mutant frequencies in splenic T-lymphocytes were significantly more enhanced in CSB^-/- mice than in control mice. The sequence data obtained from Hprt mutants indicate that B[a]P adducts at guanine residues were preferentially removed from the transcribed strand of the Hprt gene in control mice but not in CSB^-/- mice. On oral treatment with B[a]P, the tumor incidence increased in both wild-type and CSB-deficient animals. However, no differences in tumor rate were observed between TCR-deficient CSB^-/- mice and wild-type mice, which is in line with the normal cancer susceptibility of CS patients. The mutagenic response at lacZ, in contrast to Hprt, correlated well with the cancer incidence in CSB^-/- mice after B[a]P treatment, which suggests that mutations in the bulk of the DNA (inactive genes) are a better predictive marker for carcinogen-induced tumorigenesis than mutations in genes that are actively transcribed. Thus, the global genome repair pathway of NER appears to play an important role in the prevention of cancer.

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